<p>G Protein activated inwardly rectifying K⁺ (GIRK) channels are inhibited during stimulation of G_q Protein-coupled receptors (G_qPCRs) by depletion of phosphatidyl-4,5-bisphosphate (PIP₂) and/or channel phosphorylation by proteinkinase C (PKC). Receptor-specific effects of G_q signaling pathways on GIRK channel activity comprise the activation of different PKC isoforms that target distinct phosphorylation sites within the GIRK4 subunit. The serine residue S¹⁹¹ in the GIRK4 subunit is an important phosphorylation site for PKC which contributes to GIRK channel inhibition. Until now, the specific PKC isoform that phosphorylates this residue is unknown. Furthermore, the functional impact of S¹⁹¹ for G_q-receptor-specific GIRK channel modulation has not been investigated. To evaluate the contribution of this PKC phosphorylation site to receptor-specific GIRK channel modulation, we monitored the activity of phosphorylation-deficient GIRK4 (S191A) channel mutants during stimulation of adrenergic α_1B-receptors (α_1B-ARs) or Angiotensin AT₁-receptors. G_qPCR-dependent modulation of GIRK currents was analyzed in voltage-clamp experiments in rat atrial myocytes and in CHO cells expressing phosphorylation-deficient GIRK channels of various subunit compositions. As a novel finding, we demonstrate that the inhibition of phosphorylation-deficient GIRK4 (S191A) channels is impaired during stimulation of AT₁-Rs, indicating that this phosphorylation site is targeted at least by the Angiotensin II-activated PKCε isoform. In contrast, ablation of the S¹⁹¹ phosphorylation site does not attenuate phenylephrine-induced GIRK reduction, suggesting that S¹⁹¹ is not a primary target for the α_1B-AR activated PKCα. Our data indicate that the different G_qPCR-activated PKC isoforms target distinct phosphorylation sites within the GIRK4 subunit, resulting in receptor-specific regulation of the phosphorylation-deficient GIRK4 (S191A) channel mutant.</p>